Hypercholesterolemia is a contributory factor in the development of atherosclerosis and subsequent heart disease. Understanding the regulation of cholesterol synthesis should contribute to the design of methods for the prevention, detection, and treatment of hypercholesterolemia. We will continue our study of the rate limiting enzyme in cholesterol synthesis HMG-CoA reductase (HMGR) on two fronts: (1) modulation of its catalytic efficiency in rat liver, (2) regulation of its activity in leukocytes. Physiological variation in hepatic HMGR activity in rodents is achieved by altering both its rate of synthesis and its catalytic efficiency. We observe reversible effects on catalytic efficiency of HMGR in vitro by separable factors from rat liver which promote either inactivation in the presence of Mg-nucleotides or subsequent reactivation. We will (a) determine if these factors participate in physiological modulation, (b) purify these factors to homogeneity, and (c) determine the mechanisms of their action. Leukocytes show promise of being useful for studying the regulation of cholesterol synthesis in humans. They contain HMGR activity which, although very low, is regulated in at least some major respects like that in liver. For biochemical studies, they have the advantage over liver of being readily obtained from humans. We will (a) compare the regulation of HMGR in leukocytes and in liver in rats and (b) determine if some factors which affect serum cholesterol level in humans do so by affecting HMGR activity.